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Acute Respiratory Dysfunction

Pathophysiology of the Systemic Inflammatory Response Syndrome and Sepsis

INTRODUCTION AND EPIDEMIOLOGY

Sepsis continues to be the leading cause of death among children worldwide, accounting for more than 5.9 million deaths per year according to data from the World Health Organization and the United Nations Children’s Fund. In the United States, sepsis poses a significant healthcare burden with approximately 75,000 children admitted annually to hospitals with severe sepsis and an associated cost of $4.8 billion. Understanding the pathophysiology of systemic inflammatory response syndrome (SIRS) and sepsis syndrome is essential for recognition and management of this deadly disease.

PATHOGENESIS OF SEPSIS

In the 1990s, Bone and colleagues set forth the notion that systemic inflammation due to an infection can lead to SIRS, sepsis syndrome, multiple organ dysfunction syndrome (MODS), and multiple organ failure (MOF). Typically, after sensing an invading pathogen, the host’s innate immune system is locally activated in order to eradicate the infection. This immune activation is mediated by pathogen-associated molecular patterns (PAMPS), such as lipopolysaccharides from bacterial cell walls that interact with the pattern recognition receptors (PRRS) such as toll-like receptors (TLRs), which are present on local immune cells. This initial interaction between PAMPS and PRRS will lead to a signaling cascade, resulting in inflammatory cytokine and chemokine synthesis and release. Injured and dying cells caused by this inflammation go on to release damage-associated molecular patterns (DAMPS) such as the intracellular protein high-mobility group box 1. DAMPS released from tissue injury amplify the cytokine response to PAMPS that can progress into a vicious cycle of tissue and organ injuries (Fig. 97-1). The inflammatory mediators synthesized and released during sepsis syndrome are meant to help the host in combating the invading pathogen. However, if unregulated, these inflammatory mediators can induce a pathologic state of shock in the host. Shock is defined as a state of cellular and tissue hypoxia due to reduced oxygen delivery and/or increased oxygen consumption or inadequate oxygen utilization. For example, the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1beta can both (1) depress myocardial function and (2) pathologically vasodilate blood vessels partly through mechanisms of nitric oxide generation, both of which cause low blood perfusion to tissues. TNF-α also causes vascular leak syndrome by triggering the shedding of glycocalyx, which disrupts the endothelial cell lining. Glycocalyx, a multicomponent layer consisting of proteoglycans and glycoprotein that lines the luminal membrane of the endothelium, is essential in regulating vascular permeability and barrier function, hemostasis, vasomotor control, and immunological function. Thus, sepsis can cause significant disturbance in all organs, which can result in cardiovascular collapse, respiratory failure, immune dysregulation, acute kidney injury, coagulopathy, thrombotic microangiopathy, ischemic hepatitis, endotheliopathy, and mitochondrial dysfunction. The severity of these disturbances depends on many factors, including the genetic and environmental factors of both the host and the pathogen.